Monoclonal antibodies have immense potential for use as prophylactic, diagnositc, and therapeutic agents in the treatment of various types of human ailments. For many uses it is desireable to use human monoclonal antibodies as opposed to murine monoclonal antibodies. Although many approaches have been attempted to produce human monoclonal antibodies, serious limitations have been encountered. The aim of the proposed research plan is to introduce human antibody genes into mice and to utilize the resultant transgenic mice to efficiently produce human monoclonal antibodies. Three questions will be addressed: 1) Will a germline mouse immunoglobulin gene, which has been introduced into a transgenic mouse, undergo invivo rearrangement, somatic mutation, and heavy chain class switching? 2) Is there a functional relationship between homologous mouse and human variable region genes? 3) Will human germline immunoglobulin genes behave similarily to murine immunoglobulin genes when introduced into transgenic mice?